The perception, transmission and regulation of the nociceptive influxes are dependent on several endogenous neuraltransmitters. In 1975, Hugues et al. (Nature, 258, 577, 1975) have identified enkephalines, two primitively isolated pentapeptides of mammal brains which are implicated in the transmission of painful influx. Enkephalines connect with at least two classes of receptors: the opioid sites a and 6 (Pert, Sciences, 179, 1011, 1973) whose roles and locations are different. Their antinociceptive properties have been demonstrated by Belluzi et al., Nature, 260, 625, 1976. However, the analgesia induced by administration of exogenous enkephalines is very fleeting, because of the rapid metabolism of these peptides. Analogous enkephalines rendered resistant to enzymatic degradation by chemical modifications, have been synthesized, but their secondary effects are analogous to those of morphine.
The enkephalines are physiologically degraded by two types of enzymatic activity which metabolize in vivo the enkephalines: neutral endopeptidase (EC 3.4.24.11, also called NEP) which cuts the Gly3Phe4 bond and aminopeptidase N (EC 5 3.4.11.2, also called APN) which cuts the Tyr1-Gly2 bond (reviewed in Roques et al., Pharmacol. Rev., 45, 87-146, 1993).
There are known prodrugs described in European patent EP 0 487 620 and in Fournixc3xa9-Zaluski et al., J. Med. Chem., 35, 2473, 1992, which have analgesic and antidepressive activities after intravenous administration or by oral route (Noble et al., J. Pharm. Exp. Ther., 261, 181, 1992; Baamonde et al., Eur. J. Pharmacol., 216, 157, 1992). However, these compounds do not respond to the concept of mixed inhibitors, because of their structure in which an APN inhibitor and an NEP inhibitor are is associated with a disulfide bridge. These compounds are then reduced by cerebral reductases and each act on its particular target.
According to the patent application WO 95/35302 and Bioorganic and Medicinal Chemistry Letters, Vol. 6, No. 11, pp. 1257-1260, 1996, there are known certain derivatives of phosphenic acid having respectively an inhibiting activity on the enzyme conversion of endotheline (ECE) and a mixed inhibitory activity of the enzyme of conversion of angiotensin (ACE) and of neutral endopeptidase (NEP). These compounds are useful in the treatment of cardiovascular maladies.
Derivatives of xcex1-aminophosphino peptides are described in the patent application PCT/FR9701884.
One of the objects of the invention is to provide new compounds, which behave as true mixed inhibitors of APN and NEP, capable of conjointly inhibiting the two enzymatic activities responsible for the degradation of the enkephalines and to manifest their pharmacological properties after intravenous or subcutaneous injection, or by oral route (per os).
These compounds have certain properties of the morphine substances, in particular analgesia, the beneficial effects on the behavior (antidepressants, sedatives, anxiolytics, desinhibitors and promnesics), and peripheral effects (antidiuretic, antitussive, hypotensive, anti-inflammatory . . .). Moreover, an advantage of these compounds is that they have no undesirable morphine effects (tolerance, physical and psychic dependence, respiratory depression, intestinal statis . . .).
The compounds can also be used as a treatment for substitution in the toxiconomy of opioides.
The present invention has for its object compounds derived from xcex1-aminophosphino peptides of the general formula 
in which
R1 and R2 each represent a hydrogen atom or R1 and R2, taken together, form an unsaturated group of the formula Rxe2x80x2 (Rxe2x80x3)Cxe2x95x90, in which
Rxe2x80x2 represents a phenyl group in position 2 monosubstituted with a hydroxy group or a disubstituted phenyl group, in position 2, with a hydroxy group and, in position 4 or 5, either by a halogen atom or by a nitro group, or by a hydroxy group, or by an alcoxy group xe2x80x94OR9,
Rxe2x80x3 represents a phenyl group, a phenyl group substituted with 1 to 5 halogen atoms or an aromatic heterocyclic group, in what follows, the terms R9 and R10, used for the definition of the radicals, each represent an alkyl group of 1 to 6 carbon atoms,
R3 represents
a hydrogen atom,
an alkyl group or an alkenyl group of 1 to 6 carbon atoms, these two latter groups can be substituted by:
a hydroxy group or an alcoxy group xe2x80x94OR9,
a phenyl group or a benzyl group,
a sulfanyl group, an alkylsulfanyl group xe2x80x94SR9 or an alkylsulfanyl group oxidized at the sulfur atom xe2x80x94S(O)R9,
an amino group, an xe2x80x94NHR, group or xe2x80x94NR9R10 group, if desired oxidized at the nitrogen atom or,
a guanidino group H2Nxe2x80x94C(xe2x95x90NH) xe2x80x94NHxe2x80x94,
a cycloalkyl or cycloalkylmethyl group,
a phenyl group, a benzyl group, which can be substituted on the phenyl group with 1 or 2 of the following substituents:
a halogen atom,
a hydroxy group, an alcoxy group xe2x80x94OR9,
an alkylsulfanyl group xe2x80x94SR9 or an alkylsulfanyl group oxidized at the sulfur atom,
an amino group or a xe2x80x94NHR9 or xe2x80x94NR9R10 group if desired oxidized at the nitrogen atom,
a nitro group,
a phenyl group,
an alkyl group of 1 to 4 carbon atoms,
a methyl group substituted by an aromatic or saturated heterocyclic group, the heteroatoms being possibly oxidized in the form of N-oxide or S-oxide,
R4 represents
a xe2x80x94CH(X)xe2x80x94Oxe2x80x94C(O)xe2x80x94Y group, in which X and Y represent, independently of each other, an R9 group or a phenyl group,
a xe2x80x94CH2CH2xe2x80x94Sxe2x80x94C(O)xe2x80x94W group, in which W represents an R9 group or
a phenyl group,
R5 represents
a hydrogen atom,
an alkyl group or an alkenyl group of 1 to 6 carbon atoms, these two latter groups being possibly substituted with:
a hydroxy group or an alcoxy group xe2x80x94OR9,
a phenyl group or a benzyl group,
a sulfanyl group, an alkylsulfanyl group xe2x80x94SR9 or an alkylsulfanyl group oxidized at the sulfur atom xe2x80x94S(O)R9,
an amino group, an xe2x80x94NHR9 or xe2x80x94NR9R10 group, possibly oxidized at the nitrogen atom or,
a guanidino group H2Nxe2x80x94C(xe2x95x90NH) xe2x80x94NHxe2x80x94,
a cycloalkyl or cycloalkylmethyl group,
a phenyl group, a benzyl group, which can be substituted at the phenyl group by 1 or 2 of the following substituents:
a halogen atom,
a hydroxy group, an alcoxy group xe2x80x94OR9,
an alkylsulfanyl group xe2x80x94SR9 or an alkylsulfanyl group oxidized at the sulfur atom,
an amino group or an xe2x80x94NHR9 or xe2x80x94NR9R10 group which can be oxidized at the nitrogen atom,
a nitro group,
a phenyl group,
an alkyl group of 1 to 4 carbon atoms,
a methyl group substituted with a heterocyclic group, the hetero atoms can be oxidized in the form of N-oxide or S-oxide,
R6 and R7 represent independently of each other
a hydrogen atom,
an alkyl or alkenyl group of 1 to 6 carbon atoms, which can be substituted with:
a hydroxy or an alcoxy group xe2x80x94OR9,
a sulfanyl group, an alkylsulfanyl group xe2x80x94SR9 or an alkylsulfanyl group oxidized at the sulfur atom xe2x80x94S(O)R9,
an amino group or an alkylamino group xe2x80x94NHR9,
a guanidino group H2Nxe2x80x94C(xe2x95x90NH) xe2x80x94NHxe2x80x94or,
a carboxy group or an alkyloxycarbonyl group xe2x80x94COOR9,
a phenyl group, a benzyl group, which can be substituted on the phenyl group by 1 or 2 of the following substituents:
a halogen atom,
a phenyl group,
a hydroxy group or an alcoxy group xe2x80x94OR9,
an alkylsulfanyl group xe2x80x94SR9 or an alkylsulfanyl group oxidized at the sulfur atom xe2x80x94S(O)R9,
R6 and R7 together represent a saturated or unsaturated cyclic compound of 5 or 6 members, comprising 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen,
R8 represents,
an alkyl or alkenyl group of 1 to 6 carbon atoms,
a phenyl group, a benzyl group,
n is equal to 0 or 1.
Within the scope of the invention, the following terms have the following meanings:
an alkyl group is a hydrocarbon chain, saturated, linear or branched,
an alkenyl group is a linear or branched hydrocarbon chain, comprising an unsaturation,
a cycloalkyl group is a cyclic hydrocarbon chain comprising 3 to 7 carbon atoms,
a cycloalkylalkyl group is a cycloalkyl group connected to an alkyl group, this alkyl group comprising 1 to 6 carbon atoms,
a cycloalkylmethyl group is a cycloalkyl group connected to a methyl group,
a heterocyclic group is a cyclic hydrocarbon chain, aromatic or not, with 5 or 6 members, comprising 1 or 2 heteroatoms selected from atoms of oxygen, sulfur or nitrogen.
Within the scope of the invention, the halogen atoms are preferably chlorine and fluorine.
When a phenyl group is substituted with a phenyl group, it is then preferably in position 4 to form a biphenyl group (also written: (1,1xe2x80x2-biphenyl).
The present invention also has for its object addition salts of pharmacologically acceptable acids of compounds of formula (I) in which R1 and R2 are hydrogen atoms.
A preferred category of compounds according to the invention is that in which the radicals of formula (I) have the following meanings:
R1 and R2 represent hydrogen atoms,
n is equal to 0,
R3 represents
a hydrogen atom,
an alkyl group of 1 to 6 atoms of carbon, which can be substituted with a hydroxy group, an alcoxy group xe2x80x94OR9, a sulfanyl group or an alkylsulfanyl group xe2x80x94SR9,
a phenyl group, a benzyl group which can be substituted on the phenyl group with a halogen atom, an alkyl group of 1 to 4 carbon atoms, a hydroxy group, an alcoxy group xe2x80x94OR9 or an alkylsulfanyl group xe2x80x94SR9,
R4 represents
a xe2x80x94CH(X)xe2x80x94Oxe2x80x94C(O)xe2x80x94Y group, in which X and Y represent, independently of each other, an R9 group or a phenyl group,
a xe2x80x94CH2CH2xe2x80x94Sxe2x80x94C(O)xe2x80x94W group, in which W represents an R9 group or a phenyl group,
R5 represents
a phenyl group, a benzyl group, which can be substituted on the phenyl group with a halogen atom, an alkyl group of 1 to 4 carbon atoms, a hydroxy group, an alcoxy group xe2x80x94OR9 or an alkylsulfanyl group xe2x80x94SR9,
a biphenylmethyl group,
R6 represents an alkyl group of 1 to 6 carbon atoms, which can be substituted with a hydroxy group, an alcoxy group xe2x80x94OR9, a sulfanyl group or an alkylsulfanyl group xe2x80x94SR9,
R8 represents
an alkyl group of 1 to 6 carbon atoms,
a phenyl group, a benzyl group.
The compounds of formula (I) can have 1 to 5 chiral atoms on the skeleton and if desired 1 to 3 chiral atoms on the different groups of R3 to R9. The compounds of the invention can exist in different isomeric forms including the form of an enantiomers and diastereoisomers. The present invention comprises these different forms as well as their mixtures, including racemic mixtures.
The carbon bearing the R6 radical, when R6 is different from the hydrogen atom, is preferably of the absolute configuration (S).
The compounds of the invention of formula (I) can be prepared according to the processes described in annexes 1, 2 and 3.
In the description of the process, the radicals A1 and A2 have the following meanings:
A1 represents a biphenylmethyl group, a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Bzc or Z) or a fluorenylmethoxycarbonyl group (Fmoc),
A2 represents a tert-butoxycarbonyl group (Boc) or a fluorenylmethoxycarbonyl group (Fmoc).
tBu represents a tert-butyl group and Bn represents a benzyl group.
The compounds of formula (Ia) and (lb), which are compounds of the formula (I) according to the invention, are prepared according to the process represented in annex 1. R3, R4, R5, R6, R7, R8, Rxe2x80x2, Rxe2x80x3 and n have the meanings given in formula (I). According to this process, a derivative of hydroxyphosphinylpropanoic acid of formula (IVb) is reacted with an amino acid derivative of formula (V), in the presence of benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) or else of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide methiodide (EDC), in an organic solvent such as dimethylformamide. The compound of formula (V) can be used in the form of a salt, such as the salt of p-toluenesulfonic acid. It is then particularly advantageous to work in the presence of a base such as a tertiary amine such as diisopropylethylamine. This reaction permits obtaining a compound of formula (III).
The compound of formula (III) is used to prepare the compound of formula (II), in which the three amine, phosphinate and carboxylate functions are protected simultaneously. The compound of formula (III) can be treated in an organic solvent such as tetrahydrofuran, with an alcohol of the formula R4OH, in the presence of N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) to obtain the compound of formula (II).
Alternatively, the compound of formula (III) can be transformed into the cesium salt by the action of cesium A carbonate. This obtained salt can then be treated, in an organic solvent such as dimethylformamide (DMF), with a halogenated derivative R4Z, in which Z represents a halogen atom such as bromine, chlorine or iodine, to obtain the compound of formula (II).
To prepare the compound of formula (Ia), the protective group of the amine function is removed. If A2 is a tert-butoxycarbonyl group, the removal of the protective group can be carried out in a weak acid medium, such as formic acid. If A2 is a fluorenylmethoxycarbonyl group, the removal of the protective group can be carried out in a basic medium such as piperidine.
To prepare the compound of formula (Ib), a ketone Rxe2x80x2(Rxe2x80x3)Cxe2x95x90O is condensed on a compound of formula (Ia), these Rxe2x80x2(Rxe2x80x3)Cxe2x95x90O ketones being obtained by Fries rearrangement of the corresponding Rxe2x80x3CO2Rxe2x80x2 esters.
The compounds of formula (V), in which n can be equal to 0 or 1, R6, R7 and R8 have one of the meanings given in formula (I), represent an xcex1 or a xcex2 amino acid which is natural or not. They can be synthesized according to conventional methods well known to those skilled in the art.
The compounds of formula (IVb) can be prepared according to the processes described in annexes 2 and 3.
According to diagram 1, annex 2, a derivative of phosphinic acid of formula (VIII) is added to a derivative of acrylic ester of formula (VII) , in the presence of N,O-bis trimethylsilyl acetamide, without a solvent or in an inert organic solvent such as acetonitrile, to obtain the compound of formula (VI). If A1 is a biphenyl methyl or benzyloxycarbonyl group, removal of a protective group in bromohydric acid medium exposes the amine function which is then reprotected by a tert-butoxycarbonyle group or a fluorentylmethoxycarbonyle group according to processes well known to those in the art, to obtain the compound of formula (IVa). obtaining the compound of formula (IVb) from the compound of formula (IVa) is a conventional saponification or hydrolysis in acid medium.
In the case in which R5 represents the final product of formula (I), a biphenylmethyl group, there is used, according to a modification, a compound of formula (VI), in which the radical R5 represents first of all a 4-bromophenyl methyl group. This obtained compound is reacted with phenyIboronic acid in a solvent, such as a toluene/methanol mixture, and in the presence of tetrakis triphenylphosphine palladium and sodium carbonate to obtain the compound of formula (VI), in which R5 is a biphenylmethyl group.
The compound of formula (VIII) is obtained by indirect or direct synthesis, represented in diagram 2 of annex 2:
by the indirect route, the process consists in treating the diphenylmethylamine with phosphonous acid and is reacting the obtained phosphonous acid salt of diphenylmethylamine, with an aldehyde R3CHO in anhydrous ethanol to obtain a compound of formula (IX). The amine function of this compound of formula (IX) is if desired then subjected to removal of its protective group in water acidified with a mineral acid, such as hydrochloric acid or bromohydric acid, then the obtained compound is treated with propylene oxide and finally acylated to obtain a compound of formula (VIII),
by the direct route, the process consists in treating the diphenylmethylamine chlorohydrate with phosphonous acid and an aldehyde R3CHO, this reaction being carried out in a mixture of ethanol with water with reflux.
The compounds of formula (VII) can be obtained by two methods, which are represented in annex 3, respectively in diagrams 3 and 4:
according to the first process (diagram 3), a halide, preferably a bromide, of alkyl or aralkyl R5Z is erected with the triethylphosphonoacetate, in the presence of sodium hydride, to obtain the compound of formula (X), which is reacted with formaldehyde, in the presence of potassium carbonate, to obtain a compound of formula (VII).
according to the second process (diagram 4), there are obtained compounds of formula (VII) by a Mannich reaction on a monoester of a malonic acid of formula (XI).
The compounds of general formula (I), thus obtained, are in the form of isomers, including in the form of enantiomers, diastereoisomers and mixtures of these different forms, including racemic mixtures.
The compounds of formula (I), optically pure, can be obtained by separation with semi-preparative HPLC (Chromasil C8, 10 mm, 20xc3x97250 mm, acetonitrile-water, 15 ml/min).
The compounds of formula (I), optically pure, can also be obtained by resolution from a chiral amine and from the derivative of phosphinic acid to formula (VIII), then if desired by Michael diastereoselective addition, in the presence of chiral inductors, which lead to compounds of formula (VI), which have a perfectly defined stereochemistry.
The compounds of formula (I), optically pure, can finally be obtained by resolution or by enzymatic resolution of the synthesis intermediaries (VI), (IVa) or (IVb).
The separations envisaged above can be carried out on a semi-preparative column of Chromasil C8, (10 mm, 20xc3x97250 mm, 15 ml/min) with an acetonitrile/water mixture.
The following examples have for their object to illustrate the preparation of several compounds of the invention. The elementary analyses and the NMR spectra confirm the structures of the obtained compounds.
In the names of the compounds, the xe2x80x9cxe2x80x94xe2x80x9d forms a part of the word, and the xe2x80x9c_xe2x80x9d serves only to show a break at the end of the line; if there is no break in the end of the line, it is to be omitted and not replaced by a normal dash nor by a space.
In the following examples, the amino acids used during these syntheses have an absolute configuration (S).
As to the nomenclature of the compounds described in the examples which follow, according to convention, there is not indicated the configuration of the phosphorus.